Bioactive Compounds from Terrestrial and Marine-Derived Fungi of the Genus Neosartorya

Fungi comprise the second most species-rich organism group after that of insects. Recent estimates hypothesized that the currently reported fungal species range from 3.5 to 5.1 million types worldwide. Fungi can grow in a wide range of habitats, from the desert to the depths of the sea. Most develop in terrestrial environments, but several species live only in aquatic habitats, and some live in symbiotic relationships with plants, animals, or other fungi. Fungi have been proved to be a rich source of biologically active natural products, some of which are clinically important drugs such as the β-lactam antibiotics, penicillin and cephalosporin, the immunosuppressant, cyclosporine, and the cholesterol-lowering drugs, compactin and lovastatin. Given the estimates of fungal biodiversity, it is easy to perceive that only a small fraction of fungi worldwide have ever been investigated regarding the production of biologically valuable compounds. Traditionally, fungi are classified primarily based on the structures associated with sexual reproduction. Thus, the genus Neosartorya (Family Trichocomaceae) is the telemorphic (sexual state) of the Aspergillus section known as Fumigati, which produces both a sexual state with ascospores and an asexual state with conidiospores, while the Aspergillus species produces only conidiospores. However, according to the Melbourne Code of nomenclature, only the genus name Aspergillus is to be used for both sexual and asexual states. Consequently, the genus name Neosartorya was no longer to be used after 1 January 2013. Nevertheless, the genus name Neosartorya is still used for the fungi that had already been taxonomically classified before the new rule was in force. Another aspect is that despite the small number of species (23 species) in the genus Neosartorya, and although less than half of them have been investigated chemically, the chemical diversity of this genus is impressive. Many chemical classes of compounds, some of which have unique scaffolds, such as indole alkaloids, peptides, meroterpenes, and polyketides, have been reported from its terrestrial, marine-derived, and endophytic species. Though the biological and pharmacological activities of a small fraction of the isolated metabolites have been investigated due to the available assay systems, they exhibited relevant biological and pharmacological activities, such as anticancer, antibacterial, antiplasmodial, lipid-lowering, and enzyme-inhibitory activities.


Introduction
The serendipitous discovery of penicillin by Alexander Fleming in 1928, as a bioactive principle from the culture broth of Penicillium notatum that inhibited the growth of Grampositive bacteria, and its introduction in 1941 as an efficient antibacterial therapeutic without The extract of marine-derived N. pseudofischeri (collection no. 2014F27-1), isolated from the inner tissue of a sea star (A. planci), was collected from Hainan Sanya National Coral Reef Reserve, China, and cultured in glucose-peptone-yeast extract medium, furnishing N-methyl-1H-indole-2-carboxamide (6) (Figure 1) [22].

1,4-Diketopiperazine-containing Prenylated Indoles
The indole 1,4-diketopiperazine-containing prenylated indoles are a large group of indole alkaloids reported from members of the genus Neosartorya. Most of the isolated compounds are pentacyclic, but tetra-or hexacyclic compounds were also reported. They can be mono-, di-or triprenylated. Normally, the 1,4-diketopiperazine moiety is linearly fused with a pyrrolidine ring to form a hexahydropyrrolo [1,2-a]pyrazine-1,4-dione ring system, evidencing the incorporation of the amino acid proline in their biogenesis.

1,4-Diketopiperazine-containing Prenylated Indoles
The indole 1,4-diketopiperazine-containing prenylated indoles are a large group of indole alkaloids reported from members of the genus Neosartorya. Most of the isolated compounds are pentacyclic, but tetra-or hexacyclic compounds were also reported. They can be mono-, di-or triprenylated. Normally, the 1,4-diketopiperazine moiety is linearly fused with a pyrrolidine ring to form a hexahydropyrrolo [1,2-a]pyrazine-1,4-dione ring system, evidencing the incorporation of the amino acid proline in their biogenesis.

Quinazolinone-Containing Prenylated Indoles
Pseudofischerine (36) ( Figure 5), an unreported quinazolinone-containing prenylated indole, was isolated from a culture extract of N. pseudofischeri KUFC 6422 S. W. Peterson, obtained from soil planted with rose apples (Eugenia javanica, family Myrtaceae) from Angthong Province, Thailand, and cultured in a cooked rice solid medium [35]. The structure of the compound was established by the interpretation of high-resolution mass spectrum (HRMS) and 1-dimensional (1D) and 2-dimensional (2D) NMR data. The relative stereochemistry of 36 was established, based on the NOESY correlations from H-5a to OH-9a, H-12, Me-13, Me-14, H-6′, as well as via comparison with the structure of the previously described chaetominine, isolated from the endophytic fungus Chaetomium sp. IFB-E015, the stereochemistry of which was established by single-crystal X-ray analysis and the determination of the aminoacid L-Ala using Marfey's method [36]. Later on, Liao et al. reported the isolation of isochaetominine C (37) from a culture extract of the marinederived Aspergillus sp. (strain number F452). Surprisingly, the 1 H and 13 C NMR data of 37 and 36 (both in DMSO-d6) were nearly identical; however, the stereochemistry of 37 was enantiomeric of 36. Since the configurations of C-5a, C-8, C-9a and C-11 in 37 were determined by NOESY correlations and an identification of the amino acid L-Val using an

Quinazolinone-Containing Prenylated Indoles
Pseudofischerine (36) (Figure 5), an unreported quinazolinone-containing prenylated indole, was isolated from a culture extract of N. pseudofischeri KUFC 6422 S. W. Peterson, obtained from soil planted with rose apples (Eugenia javanica, family Myrtaceae) from Angthong Province, Thailand, and cultured in a cooked rice solid medium [35]. The structure of the compound was established by the interpretation of high-resolution mass spectrum (HRMS) and 1-dimensional (1D) and 2-dimensional (2D) NMR data. The relative stereochemistry of 36 was established, based on the NOESY correlations from H-5a to OH-9a, H-12, Me-13, Me-14, H-6 , as well as via comparison with the structure of the previously described chaetominine, isolated from the endophytic fungus Chaetomium sp. IFB-E015, the stereochemistry of which was established by single-crystal X-ray analysis and the determination of the aminoacid L-Ala using Marfey's method [36]. Later on, Liao et al. reported the isolation of isochaetominine C (37) from a culture extract of the marine-derived Aspergillus sp. (strain number F452). Surprisingly, the 1 H and 13 C NMR data of 37 and 36 (both in DMSO-d 6 ) were nearly identical; however, the stereochemistry of 37 was enantiomeric of 36. Since the configurations of C-5a, C-8, C-9a and C-11 in 37 were determined by NOESY correlations and an identification of the amino acid L-Val using an advanced Marfey's method [37], the absolute configurations of its stereogenic carbons were established. Therefore, 36 and 37 are the same compound. Later on, Lan et al. [21] reported the isolation of isochaetominine C (37) from a culture extract of N. pseudofischeri, isolated from the inner tissue of a starfish (A. planci) that was collected from the Hainan Sanya National Coral Reef Reserve, China, and cultured in a liquid medium. However, the stereochemistry of the structure of isochaetominine C reported in this paper is opposite to that reported by Liao et al. [37]. Compound 37 was also isolated from N. pseudofischeri [38] and also from N. hiratsukae [39]; both samples were collected from soil in the Chiang Mai forest, Thailand, and cultured in a potato dextrose liquid medium.
reported the isolation of isochaetominine C (37) from a culture extract of N. pseudofischeri, isolated from the inner tissue of a starfish (A. planci) that was collected from the Hainan Sanya National Coral Reef Reserve, China, and cultured in a liquid medium. However, the stereochemistry of the structure of isochaetominine C reported in this paper is opposite to that reported by Liao et al. [37]. Compound 37 was also isolated from N. pseudofischeri [38] and also from N. hiratsukae [39]; both samples were collected from soil in the Chiang Mai forest, Thailand, and cultured in a potato dextrose liquid medium.
Three previously unreported reverse prenylated indole alkaloids analogs of (-)ardeemins, sartoryglabrins A (38), B (39) and C (40) (Figure 5), were isolated from an extract of a solid culture medium (cooked rice) of N. pseudofischeri, which was collected from soil in Chonburi Province, Thailand. The structures of the compounds were elucidated by analysis of HRMS, 1D and 2D NMR data. The absolute structure of 38 was established by X-ray analysis, using CuKα radiation [40].

Anellated Indoles
Like prenylated indoles, anellated indoles also constitute a large group of specialized metabolites reported from both terrestrial and marine-derived Neosartorya species. Their structures vary from simple to complex, and some of them incorporate sulfur atoms to form a disulfide bridge.

Anellated Indoles
Like prenylated indoles, anellated indoles also constitute a large group of specialized metabolites reported from both terrestrial and marine-derived Neosartorya species. Their structures vary from simple to complex, and some of them incorporate sulfur atoms to form a disulfide bridge.
The previously reported tryptoquivalines F (58), H (59), L (60), and the unreported tryptoquivaline O (61) (Figure 7) were also isolated from a culture extract of the soilderived N. siamensis KUFC 6349. It is worth mentioning that Buttachon et al. [42] have established the absolute configurations of C-2, C-3, and C-12 of 60 as 2S, 3S, 12R by X-ray analysis using CuKα radiation, which was opposite to those previously reported by Yamazaki et al. [45], thus establishing unambiguously the stereostructures of the tryptoquivaline series. Another unreported tryptoquivaline analog, tryptoquivaline T (62), was isolated from a culture extract of the diseased coral-derived N. laciniosa KUFC
7896 [46]. Compounds 58-60 were also isolated from a culture extract of the marine sponge-associated N. paulistensis KUFC 7897 [46]. Compound 60 was the most common tryptoquivaline, being reported from various species and strains of Neosartorya, such as the marine-derived N. siamensis KUFCA0017 [43], the marine-derived N. laciniosa KUFC 7896 [25], and the soil-derived N. spinosa KKU-1NK1 [44]. Compound 59 was also reported from the marine-derived N. siamensis KUFA 0017 [43], the marine sponge-associated N. paulistensis KUFC 7897 [46]. Compounds 59 and 60 were isolated, together with a new tryptoquivaline analog, tryproquivaline U (63), from a culture extract of the algicolous fungus, N. takakii KUFC 7898 [29]. The unreported tryptoquivaline V (64) was isolated from a culture extract of the soilderived N. pseudofischeri [38]. It is interesting to note that the stereochemistry at C-3 of the five-membered lactone was opposite to that of all the reported tryptoquivalines. The authors determined the absolute configuration of C-3 only by NOESY correlations between key protons, some of which were not well defined, and a sign of the optical rotation. However, the authors did not use any reliable methods, such as X-ray crystallography with CuKα radiation or chiroptical methods, to determine the absolute configuration of the stereogenic carbon. The unreported tryptoquivaline V (64) was isolated from a culture extract of the soilderived N. pseudofischeri [38]. It is interesting to note that the stereochemistry at C-3 of the five-membered lactone was opposite to that of all the reported tryptoquivalines. The authors determined the absolute configuration of C-3 only by NOESY correlations between key protons, some of which were not well defined, and a sign of the optical rotation. However, the authors did not use any reliable methods, such as X-ray crystallography with CuKα radiation or chiroptical methods, to determine the absolute configuration of the stereogenic carbon.
Two tryptoquivaline derivatives, the tryptoquivalines P (65) and Q (66) (Figure 7), were isolated from the organic extract of Neosartorya sp. HN-M-3, obtained from a marine mud in the intertidal zone of Hainan Province, China, and cultured in a liquid medium containing barley sugar, ajinomoto, glucose, and yeast extract. The structures of 65 and 66 differ from other tryptoquivalines in that the five-membered lactone ring is hydrolyzed to give a hydroxy group on C-2 and a carboxylic acid on C-11. However, the absolute configurations at C-2 and C-3 were not determined [47].
The undescribed quinazolinone-containing hexacyclic indole alkaloid consisting of an azepinone ring fused with the indole ring system, named sartorymensin (68) (Figure 7), was isolated from a culture extract of the soil-derived N. siamensis KUFC 6349. The structure of 68 was established by the interpretation of HRMS and 1D and 2D NMR data. The absolute configurations at C-10 and C-13 were established unequivocally as 10S and 13S by X-ray analysis using CuKα radiation [42].

Pyrazinoquinazolinone-Containing Anellated Indoles
The compounds of this group consist of a pyrazinoquinazolinone moiety connected to the 6-5-5-imidazoindolone ring system by a methylene bridge. A culture extract of the soil-derived N. siamensis KUFC 6349 furnished the previously reported fiscalin A (69) and its undescribed diastereomers, epi-fiscalin A (70), neofiscalin A (71), and epi-neofiscalin A (72), as well as the previously reported fiscalin C (73) and the undescribed epi-fiscalin C (74) (Figure 8). The structures of 69-74 were elucidated by extensive analysis of HRMS data and 1D and 2D NMR spectral analysis. The configuration of C-3 in 70 was evidenced by a W-type long-range coupling between NH-2 and H-14 in the COSY spectrum, while the configurations of C-20 and C-22 were proved to be the same as those of 69 by a NOESY correlation from H-20 to Me-21. The stereostructures of 71 and 72 were based on a Wtype long-range coupling between NH-2 and H-14 in the COSY spectrum and the NOESY correlation from H-20 to Me-21 or H-22. The structures and configurations of the stereogenic carbons of 69-72 were corroborated by the stereostructure of 73 and 74, whose structures and the absolute configurations of the stereogenic carbons were established conclusively by X-ray analysis using CuKα radiation [42]. Compounds 69-74 were also isolated from a culture extract of the sea-fan-derived N. siamensis KUFA 0017 [43]. Shan et al. described the isolation of two undescribed norfumiquinazolines, cottoquinazolines E and F, from the ethanol extract of a solid culture (moist wheat) of N. fischeri NRRL 181 [49]. The structures of the compounds were elucidated by extensive analysis of 1D and 2D NMR and HRMS spectral data; however, the relative configurations of some stereogenic carbons were still undetermined by NOESY correlations. Recently, Lin et al. also obtained the cottoquinazolines E (84), F (85), and G (86) (Figure 9) from the organic extract of a solid rice culture of the insect-derived N. fischeri TJ 403-CA8. The  Compound 74 was also isolated, together with two unreported tryptoquivalines, E (75) and F (76) (Figure 8), from a culture extract of N. udagawae HDN 13-313 that was obtained from the root of a mangrove plant, Aricennia marina, collected from a mangrove conservation area in Hainan Province, China, and cultured in a liquid medium (composed of maltose, mannitol, glucose, monosodium glutamate, and yeast extract). The stereochemistry of 75 and 76 was established by a comparison of the calculated and experimental electronic circular dichroism (ECD) spectra. The structure and stereochemistry of 75 were also confirmed by X-ray analysis [48]. The previously reported fiscalin analog, quinadoline A (77) (Figure 8), was also isolated from the soil-derived N. spinosa KKU-1NK1 [44].

Pyridoquinazolinone-Containing Anellated Indoles
Wu et al. reported the isolation of an undescribed pyridoquinazolinone linked to 2oxindole by a spirofuran ring, together with an undescribed pyridoquinazolinone linked to the imidazolindolone moiety by a spirofuran ring, which they have named tryptoquivalines U (78) and T (79) (Figure 8), respectively. These were from a culture extract of the marinederived N. fischeri, isolated from a marine mud, which was collected in the intertidal zone of Hainan Province, China [19]. Interestingly, the authors were unaware of the existence of the previously reported tryptoquivaline T (62), isolated from a culture extract of the diseased coral-derived N. laciniosa KUFC 7896 [46], along with tryptoquivaline U (63), isolated from a culture extract of the algicolous fungus N. takakii KUFC 7898 [29], and they gave the same names to their compounds. Structurally, tryptoquivalines are a class of indole alkaloids, having a quinazolinone moiety connected to the 6-5-5-imidazoindolone ring system via a five-membered spirolactone and not a pyridoquinazolinone connected to the 6-5-5-imidazoindolone ring system via a five-membered spirolactone, which is the case with 78 and 79.
Later, Yu et al. reported the undescribed fiscalins E (80) and F (81), and two pyridoquinazolinones, linked to the imidazolindolone ring system by a spirofuran ring, which were named Neosartoryadins A (82) and B (83) (Figure 8), and were taken from a culture extract of N. udagawae HDN 13-313 [48]. The structures of both compounds were established by extensive analysis of HRMS and 1D and 2D NMR data. The absolute configurations of the stereogenic carbons in 80 and 81 were established by comparison of calculated and experimental ECD spectra. In the case of 80, the absolute structure was confirmed by X-ray analysis. The relative configurations of the stereogenic carbons in 82 and 83 were established by NOESY correlations of the key protons while the absolute configurations at C-1, C-14, C-16 and C-17 in 82 were determined as 1R, 14R, 16S, and 17R by comparison of the calculated and experimental ECD spectra. The absolute configurations at C-1, C-14, C-16 and C-17 in 83 are the same as those of 77, since both compounds displayed nearly identical ECD spectra. Interestingly, the structure of Neosartoryadin A (82) is the same as that of tryptoquivaline U (78), as reported by Wu et al. [19]. The only difference is that the configuration of C-12 in 78 is opposite to that of the same carbon (C-14) in 82.
Since the configuration of C-12 in 78 was opposite to that of the same carbon of all other imidazolindolone-containing compounds isolated from members of this genus, this raises the possibility of a wrong assignment. Shan et al. described the isolation of two undescribed norfumiquinazolines, cottoquinazolines E and F, from the ethanol extract of a solid culture (moist wheat) of N. fischeri NRRL 181 [49]. The structures of the compounds were elucidated by extensive analysis of 1D and 2D NMR and HRMS spectral data; however, the relative configurations of some stereogenic carbons were still undetermined by NOESY correlations. Recently, Lin et al. also obtained the cottoquinazolines E (84), F (85), and G (86) (Figure 9) from the organic extract of a solid rice culture of the insect-derived N. fischeri TJ 403-CA8. The structures of the compounds were established by analysis of HRMS and 1D and 2D NMR spectral data. The relative configurations of C-16, C-17 and C-19 were determined as 16S*, 17S*, and 19S* by NOESY correlations, while the absolute configurations of C-3, C-14, C-16, C-17, and C-19 were determined by X-ray analysis using CuKα radiation as 3S, 14S, 16S, 17S, and 19S, thus solving the structure and the absolute configurations of the stereogenic carbons in 84. The absolute configurations of the stereogenic carbons in 85 and 86 were determined by comparison of their calculated and experimental ECD spectra [50].
OR PEER REVIEW by molecular modeling. Compound 87 was also isolated from the mari associated N. fenelliae KU0811 [30].

Bis-Indoles
Only three bis-indoles were isolated from fungi of the genus Neosartorya. Fellutamine A (87) and the unreported fellutamine A epoxide (88) ( Figure 9) were isolated from a culture extract of the marine sponge-associated N. glabra KUFA 0702 [23]. The relative configurations of C-2 and C-3 in 88 were established by NOESY correlations, as well as by molecular modeling. Compound 87 was also isolated from the marine sponge-associated N. fenelliae KU0811 [30].

Dibenzylpiperazine Alkaloids
Although indole alkaloids are very copious in the fungi of the genus Neosartorya, dibenzylpiperazine alkaloids are very rare among the species investigated. Biosynthetically, dibenzylpiperazine alkaloids are derived from the coupling of Phe/Tyr.

Peptides
The previously reported dipeptide, (11aR)-2,3-dihydro-1H-pyrrolo [2,4c][1,4]benzodiazepine-5,11 (10H,11aH)-dione (93), and two undescribed cyclic tetrapeptides, sartoryglabramides A (94) and B (95) ( Figure 11) were isolated from a culture extract of the marine sponge-associated N. glabra KUFA 0702 [23]. The difference between 94 and 95 is that the Phe residue that linked with the anthranilic acid moiety in the former was replaced by Trp in the latter. The structures of both 94 and 95 were elucidated by extensive analysis of HRMS and 1D and 2D NMR data. The stereostructure of 94 was established by X-ray analysis using CuKα radiation, whereas the absolute configurations of the amino acid residues in 95 were determined by chiral HPLC analysis of its acidic hydrolysate, using appropriate D-and L-amino acid standards.

Peptides
The previously reported dipeptide, (11aR)-2,3-dihydro-1H-pyrrolo [2,4-c][1,4]benzodiaze pine-5,11 (10H,11aH)-dione (93), and two undescribed cyclic tetrapeptides, sartoryglabramides A (94) and B (95) ( Figure 11) were isolated from a culture extract of the marine spongeassociated N. glabra KUFA 0702 [23]. The difference between 94 and 95 is that the Phe residue that linked with the anthranilic acid moiety in the former was replaced by Trp in the latter. The structures of both 94 and 95 were elucidated by extensive analysis of HRMS and 1D and 2D NMR data. The stereostructure of 94 was established by X-ray analysis using CuKα radiation, whereas the absolute configurations of the amino acid residues in 95 were determined by chiral HPLC analysis of its acidic hydrolysate, using appropriate Dand L-amino acid standards.

Peptides
The previously reported dipeptide, (11aR)-2,3-dihydro-1H-pyrrolo [2,4c][1,4]benzodiazepine-5,11 (10H,11aH)-dione (93), and two undescribed cyclic tetrapeptides, sartoryglabramides A (94) and B (95) ( Figure 11) were isolated from a culture extract of the marine sponge-associated N. glabra KUFA 0702 [23]. The difference between 94 and 95 is that the Phe residue that linked with the anthranilic acid moiety in the former was replaced by Trp in the latter. The structures of both 94 and 95 were elucidated by extensive analysis of HRMS and 1D and 2D NMR data. The stereostructure of 94 was established by X-ray analysis using CuKα radiation, whereas the absolute configurations of the amino acid residues in 95 were determined by chiral HPLC analysis of its acidic hydrolysate, using appropriate D-and L-amino acid standards.

Meroterpenoids
Meroterpenoids constitute a large group of specialized metabolites from Neosartorya species. They are structurally diverse and can be grouped according to the type of terpenoids, such as sesquiterpenes and diterpenes. Within the terpenoid class, they can be grouped according to a non-terpenoid moiety.

Merosesquiterpenes
The first group of merosesquiterpenes is of the pyripyropenes and phenylpyripyropenes. In this group, the non-terpenoid moiety is derived from polyketides. The difference between these two groups is the presence of a pyridine ring in the former and a phenyl group in the latter. Several pyripyropenes with varying substituents have been reported from N. fischeri and N. pseudofischeri.

Meroterpenoids
Meroterpenoids constitute a large group of specialized metabolites from Neosartorya species. They are structurally diverse and can be grouped according to the type of terpenoids, such as sesquiterpenes and diterpenes. Within the terpenoid class, they can be grouped according to a non-terpenoid moiety.

Merosesquiterpenes
The first group of merosesquiterpenes is of the pyripyropenes and phenylpyripyropenes. In this group, the non-terpenoid moiety is derived from polyketides. The difference between these two groups is the presence of a pyridine ring in the former and a phenyl group in the latter. Several pyripyropenes with varying substituents have been reported from N. fischeri and N. pseudofischeri.
Compound 113 can be hypothesized as a biosynthetic precursor of 115, as shown in Figure 15. The nucleophilic addition of the methylamino group on C-2 to the aldehyde carbonyl (C-5), with a concomitant addition of the aldehyde oxygen to the carbonyl carbon attached to the benzene ring (C-4) in 113, leads to the formation of an intermediate contain- Compound 113 can be hypothesized as a biosynthetic precursor of 115, as shown in Figure 15.

Meroditerpenes
All the meroditerpenes isolated from members of the genus Neosartorya have polyketides with a variable number of acetate units in a non-terpenoid moiety. The most common diterpenoid moiety is tricyclic, but bicyclic, monocyclic, or even linear diterpenes have also been reported. They can be divided into three subgroups, according to the structure of the polyketide moiety. .. 2 2' 3'  Compound 113 can be hypothesized as a biosynthetic precursor of 115, as shown in Figure 15.

Meroditerpenes
All the meroditerpenes isolated from members of the genus Neosartorya have polyketides with a variable number of acetate units in a non-terpenoid moiety. The most common diterpenoid moiety is tricyclic, but bicyclic, monocyclic, or even linear diterpenes have also been reported. They can be divided into three subgroups, according to the structure of the polyketide moiety. ..

Meroditerpenes
All the meroditerpenes isolated from members of the genus Neosartorya have polyketides with a variable number of acetate units in a non-terpenoid moiety. The most common diterpenoid moiety is tricyclic, but bicyclic, monocyclic, or even linear diterpenes have also been reported. They can be divided into three subgroups, according to the structure of the polyketide moiety.

Polyketides
Secondary metabolites derived from polyketides, which have diverse structural features, are the most abundant group produced by the Neosartorya species. Two previously reported cyclopentenone derivatives, terrein (150) and isoterrein (151) (Figure 20), were isolated from a culture extract of N. fischeri IFM 52672 cultured in moist rice [24]. Fischeacid (152) (Figure 20), a bis-decalin polyketide, was isolated from a culture extract of the marine-derived N. fischeri 1008F1 [55]. Fischerin (153) (Figure 20), possessing a decalin scaffold linked to a hydroxypyridone moiety by a carbonyl group, was first reported from N. fischeri var. fischeri CBM-FA-0156 [34] and, later, from a culture extract of N. fischeri JS0553 [27]. Fujimoto et al. proposed its biogenesis as being derived from Phe and a heptaketide [34]. A great number of microbial secondary metabolites containing decalin motif, with structural diversity and relevant biological activity, has been reported. Li et al. have presented an excellent review on natural products containing the decalin motif in the form of microorganisms [56]. Acetophenones were also reported from some species of Neosarirya. First, 2,6-Dihydroxy-3-methylacetophenone (154) (Figure 20) was isolated from a culture extract of the soil-derived N. siamensis KUFC 6349 [42], as well as from the marine-derived N. siamensis KUFA0017 [43]. The undescribed 2S, 4S-spinosate (155) and 2S, 4R-spinosate (156) (Figure 20) were isolated from a culture extract of N. spinosa KKU-1NK1. The absolute configurations at C-2 and C-4 in both compounds were established by the comparison of calculated and experimental ECD spectra [44].
Another group of polyketides comprises the benzofuranone derivatives. The unreported neosarphenol A (157), and the previously reported methoxyvermistatin (158), vermistatin (159), and 6-demethylvermistatin (160) (Figure 20) were isolated from a culture extract of N. glabra CGMCC32286. The absolute configuration at C-8 in 157 was determined via a comparison of the sign of its optical rotation with that of the known 158 [53]. The undescribed quadricinctone A (161) (Figure 20) was isolated from a solid rice culture extract of the marine sponge-associated fungus N. quadricincta KUFA0081. The absolute configurations at C-3 and C-10 were established as 3R, 10S by X-ray analysis   Acetophenones were also reported from some species of Neosarirya. First, 2,6-Dihydroxy-3-methylacetophenone (154) (Figure 20) was isolated from a culture extract of the soilderived N. siamensis KUFC 6349 [42], as well as from the marine-derived N. siamensis KUFA0017 [43]. The undescribed 2S, 4S-spinosate (155) and 2S, 4R-spinosate (156) ( Figure 20) were isolated from a culture extract of N. spinosa KKU-1NK1. The absolute configurations at C-2 and C-4 in both compounds were established by the comparison of calculated and experimental ECD spectra [44].
Another group of polyketides comprises the benzofuranone derivatives. The unreported neosarphenol A (157), and the previously reported methoxyvermistatin (158), vermistatin (159), and 6-demethylvermistatin (160) (Figure 20) were isolated from a culture extract of N. glabra CGMCC32286. The absolute configuration at C-8 in 157 was deter-mined via a comparison of the sign of its optical rotation with that of the known 158 [53]. The undescribed quadricinctone A (161) (Figure 20) was isolated from a solid rice culture extract of the marine sponge-associated fungus N. quadricincta KUFA0081. The absolute configurations at C-3 and C-10 were established as 3R, 10S by X-ray analysis using CuKα radiation [57]. A chromanol derivative (162) (Figure 20) was isolated from a culture extract of the marine sponge-associated fungus N. tsunodae KUFC 9213. The structure of the compound was elucidated via the analysis of HRMS and 1D and 2D NMR spectral data. The absolute configurations at C-1, C-8 and C-9 were determined as 1R, 8S, and 9R by X-ray analysis using CuKα radiation [30].
Isochromanones have been reported from both terrestrial and marine-derived Neosartorya species. (R)-6-Hydroxymellein (163) (Figure 21) was reported from a culture extract of the algicolous fungus N. takakii KUFC 7898 [29], as well as from a solid rice culture extract of the marine sponge-associated N. spinosa KUFA 1047 [58]. The undescribed quadricinctone C (164) (Figure 21) was isolated from a culture extract of the marine sponge-associated fungus N. quadricincta KUFA0081. The absolute configurations at C-3 and C-4 were established as 3S, 4R by X-ray analysis using CuKα radiation [57]. The unreported 6,8-dihydroxy-3-(1E,3E)-penta-1,3-dien-1-yl) isochroman-1-one (165) (Figure 21) was isolated from a culture extract of the starfish-derived N. pseudofischeri. Its structure was established by the interpretation of HRMS and 1D and 2D NMR data; however, their absolute configuration at C-3 was not determined [21]. The previously reported phialophoriol (166) (Figure 21) was isolated from a culture extract of N. glabra CGMCC32286 [53]. The unreported prenyl 4-hydroxybenzoic acid ester of a dihydrochromone, PF1223 (167) (Figure 21), was isolated from a culture extract of N. quadricincta strain PF1223, which was obtained from the Meiji Seika Kaisha collection and cultured in a solid medium containing raw rice and soybean meal. The structure of 167 was established by 1D and 2D NMR spectral analysis and HRMS data; however, the absolute configurations of the stereogenic carbons C-3 and C-4 were not determined [59].
The previously reported trichodermamide A (169) (Figure 21), whose structure consists of a coumarin nucleus linked to a tetrahydro 1,2-benzoxazine moiety through an amide linkage, was isolated from a culture extract of the starfish-derived N. pseudofischeri [21].
The previously reported anthraquinones, chrysophanol (170) and emodin (171) (Figure 22), were isolated from a culture extract of the marine-derived N. fischeri 1008F1 [55]. The previously reported acetylquestinol (172) was isolated as a 1:3 mixture with the undescribed acetylpenipurdin A (173), together with the previously reported penipurdin A (174) (Figure 22), from a culture extract of the marine sponge-associated N. spinosa KUFA1047 [58]. Polyhydroxylated xanthones and bis-xanthone derivatives were also reporte Neosartorya species, especially N. fischeri. The unreported fischexanthone (17 isolated, together with the previously reported sydowinins A (176) and B (177), an B4 (178) ( Figure 23) from a culture extract of N. fischeri 1008 F1 [55]. The undescrib xanthone derivative, neosartorin (179) (Figure 23), was isolated from a liquid extract of N. fischeri, isolated from sediment from the River Vah in Slovakia. The st of the compound was elucidated by extensive analysis of HRMS and 1D and 2D data. The relative stereochemistry of 179 was determined on the basis of 1 H-1 H c constants of JH-5/H-6ax (2.0 Hz) and JH-5/H-6eq (4.0 Hz), JH-6′/H-7′ax (10 Hz), as well as by obse of the nuclear Overhauser effects (NOEs) between H-2′ of the carboxymethyl gro OH-1 and OH-8, as well as between the methyl protons of COOMe on C-5′ and H The previously reported secalonic acid A (180) (Figure 23) was isolated from a extract of the marine sponge-associated N. fenelliae KUFA 0811 [30].
Another group of polyketides is the biphenyl ethers and their derivativ previously described diorcinol (181) (Figure 24) was isolated from a culture extrac soil-derived N. hiratsukae [39]. The previously reported tenellic acid (182), the unde neospinosic acid (183) and spinolactone (184), and the previously reported vermi (185) (Figure 24) were isolated from a culture extract of the marine sponge-associ spinosa KUFA 1047 [58]. Since the absolute configuration at C-8 in 182 had n established, de Sá et al. [58] determined the absolute configuration of C-8 in 182 a the comparison of its calculated and experimental ECD spectra. The structures Polyhydroxylated xanthones and bis-xanthone derivatives were also reported from Neosartorya species, especially N. fischeri. The unreported fischexanthone (175) was isolated, together with the previously reported sydowinins A (176) and B (177), and AGI-B4 (178) ( Figure 23) from a culture extract of N. fischeri 1008 F1 [55]. The undescribed bis-xanthone derivative, neosartorin (179) (Figure 23), was isolated from a liquid culture extract of N. fischeri, isolated from sediment from the River Vah in Slovakia. The structure of the compound was elucidated by extensive analysis of HRMS and 1D and 2D NMR data. The relative stereochemistry of 179 was determined on the basis of 1 H-1 H coupling constants of J H-5/H-6ax (2.0 Hz) and J H-5/H-6eq (4.0 Hz), J H-6 /H-7 ax (10 Hz), as well as by observation of the nuclear Overhauser effects (NOEs) between H-2 of the carboxymethyl group and OH-1 and OH-8, as well as between the methyl protons of COOMe on C-5 and H-3 [60]. The previously reported secalonic acid A (180) (Figure 23) was isolated from a culture extract of the marine sponge-associated N. fenelliae KUFA 0811 [30].
Another group of polyketides is the biphenyl ethers and their derivatives. The previously described diorcinol (181) (Figure 24) was isolated from a culture extract of the soil-derived N. hiratsukae [39]. The previously reported tenellic acid (182), the undescribed neospinosic acid (183) and spinolactone (184), and the previously reported vermixocin A (185) (Figure 24) were isolated from a culture extract of the marine sponge-associated N. spinosa KUFA 1047 [58]. Since the absolute configuration at C-8 in 182 had not been established, de Sá et al. [58] determined the absolute configuration of C-8 in 182 as 8S by the comparison of its calculated and experimental ECD spectra. The structures of the unreported 183 and 184 were established by extensive analysis of their HRMS and 1D and 2D NMR data. The absolute configuration at C-8 in both compounds was determined as 8S by comparison of their calculated and experimental ECD spectra.  In their study, de Sá et al. [58] proposed the biosynthetic relationship of 182-185, as depicted in Figure 25.  In their study, de Sá et al. [58] proposed the biosynthetic relationship of 182-185, as depicted in Figure 25. Two previously reported penicillide (186) and purpactin A (187) were isolated, together with the unreported neosarphenol B (188) (Figure 24), from a culture extract of N. glabra CGMCC32286 [53].
In their study, de Sá et al. [58] proposed the biosynthetic relationship of 182-185, as depicted in Figure 25.    The formyl group in X can be reduced to a primary alcohol in XI (=XII). Esterification of the carboxyl group by a primary alcohol in XI leads to the formation of 185, while esterification by a phenolic hydroxyl group in XII leads to the formation of 184.
The formyl group in X can be reduced to a primary alcohol in XI (= XII). Esterification of the carboxyl group by a primary alcohol in XI leads to the formation of 185, while esterification by a phenolic hydroxyl group in XII leads to the formation of 184.
Glabramycins A (193), B (194), and C (195) (Figure 26) are macrocyclic lactones, isolated from a solid culture extract of N. glabra (strain MF7030, F-155,700) obtained from a hot-water-pasteurized soil that was collected in Valdefresno Province in Spain. The structures of the compounds were elucidated by 1D and 2D NMR and HRMS data. However, the absolute configuration at C-20 was not determined [62].

Benzoic Acid Derivatives
Although secondary metabolites originating from benzoic acid are not ubiquitous in fungi such as indole alkaloids, meroterpenoids, and polyketides, some of them have been reported sporadically. The previously reported 3,4-dihydroxybenzoic acid (196) ( Figure  27) was isolated from a culture extract of the marine-derived N. fischeri 1008F1 [55].  (Figure 26) are macrocyclic lactones, isolated from a solid culture extract of N. glabra (strain MF7030, F-155,700) obtained from a hotwater-pasteurized soil that was collected in Valdefresno Province in Spain. The structures of the compounds were elucidated by 1D and 2D NMR and HRMS data. However, the absolute configuration at C-20 was not determined [62].

Benzoic Acid Derivatives
Although secondary metabolites originating from benzoic acid are not ubiquitous in fungi such as indole alkaloids, meroterpenoids, and polyketides, some of them have been reported sporadically. The previously reported 3,4-dihydroxybenzoic acid (196) (Figure 27) was isolated from a culture extract of the marine-derived N. fischeri 1008F1 [55]. data. The absolute configurations of the stereogenic carbons, i.e., C-2 in 197, 202, and 203 were established as 2S, 2S, and 2R, respectively, by X-ray analysis using CuKα radiation. Moreover, the Ortep view also revealed the configuration of the sulfoxide group in 201 as R. However, the configuration of C-3 in 199 and C-1′ in 204 were still undetermined. It is worth mentioning that marine natural products with methyl sulfoxide substituents, such as in 201, are not very common. The biosynthetic pathways for 197-204 were proposed to be of mixed origin, i.e., shikimic acid and mevalonic acid pathways, similar to that proposed for fomannoxin [63]. The biosynthetic pathways start with the formation of p-hydroxybenzoic acid by elimination of a pyruvate moiety from chorismate by chorismate pyruvate lyase. The prenylation of p-hydroxybenzoic acid by DMAPP leads to the formation of I, which, after epoxidation of the double bond of the prenyl group, forms II. Nucleophilic substitution of the epoxide by a phenolic hydroxyl group gives rise to 203 (route a) or III (route b). Hydroxylation of one of the methyl groups of the prenyl side chain in 203 leads to the formation of 204. Another pathway is the dehydration of III, resulting in the formation of V which, upon hydroxylation of one of the methyl groups, leads to the formation of 197. On the other hand, III can undergo dehydration, followed by regiospecific hydration and oxidation to give IV, which can be either hydroxylated at one of the methyl groups to give 202 or undergoes decarboxylation and aromatic hydroxylation to give 200. The introduction of a methyl sulphonyl group to the benzene ring results in the formation of 201 ( Figure 28) [57].  (Figure 27) were isolated from a solid rice culture extract of the marine sponge-associated N. quadricincta KUFA 0081 [57]. The structures of the compounds were established by extensive analysis of 1D and 2D NMR spectra and HRMS data. The absolute configurations of the stereogenic carbons, i.e., C-2 in 197, 202, and 203 were established as 2S, 2S, and 2R, respectively, by X-ray analysis using CuKα radiation. Moreover, the Ortep view also revealed the configuration of the sulfoxide group in 201 as R. However, the configuration of C-3 in 199 and C-1 in 204 were still undetermined. It is worth mentioning that marine natural products with methyl sulfoxide substituents, such as in 201, are not very common.
The biosynthetic pathways for 197-204 were proposed to be of mixed origin, i.e., shikimic acid and mevalonic acid pathways, similar to that proposed for fomannoxin [63]. The biosynthetic pathways start with the formation of p-hydroxybenzoic acid by elimination of a pyruvate moiety from chorismate by chorismate pyruvate lyase. The prenylation of p-hydroxybenzoic acid by DMAPP leads to the formation of I, which, after epoxidation of the double bond of the prenyl group, forms II. Nucleophilic substitution of the epoxide by a phenolic hydroxyl group gives rise to 203 (route a) or III (route b). Hydroxylation of one of the methyl groups of the prenyl side chain in 203 leads to the formation of 204. Another pathway is the dehydration of III, resulting in the formation of V which, upon hydroxylation of one of the methyl groups, leads to the formation of 197. On the other hand, III can undergo dehydration, followed by regiospecific hydration and oxidation to give IV, which can be either hydroxylated at one of the methyl groups to give 202 or undergoes decarboxylation and aromatic hydroxylation to give 200. The introduction of a methyl sulphonyl group to the benzene ring results in the formation of 201 ( Figure 28) [57]. Compound 199 is also derived from p-hydroxybenzoic acid but uses isopentenyl pyrophosphate (IPP) as a prenylating agent to form VI. The epoxidation of the terminal double bond of the isopentenyl group gives VII, which, upon the nucleophilic substitution of the epoxide by a phenolic hydroxyl group, leads to the formation of a hydroxyoxepine ring in VIII. Further desaturation of the hydroxyoxepine ring gives rise to 199 (Figure 29) [57]. Compound 199 is also derived from p-hydroxybenzoic acid but uses isopentenyl pyrophosphate (IPP) as a prenylating agent to form VI. The epoxidation of the terminal double bond of the isopentenyl group gives VII, which, upon the nucleophilic substitution of the epoxide by a phenolic hydroxyl group, leads to the formation of a hydroxyoxepine ring in VIII. Further desaturation of the hydroxyoxepine ring gives rise to 199 ( Figure 29) [57].

Miscellaneous
Nanodrides are fungal metabolites containing a nine-membered ring fused to one or two maleic anhydride moieties. Although several nanodrides have been reported from the cultures of many fungal species, only byssochlamic acid (207) (Figure 30) was isolated

Miscellaneous
Nanodrides are fungal metabolites containing a nine-membered ring fused to one or two maleic anhydride moieties. Although several nanodrides have been reported from the cultures of many fungal species, only byssochlamic acid (207) (Figure 30) was isolated from cultures of the marine sponge-associated N. fenelliae KUFA 0811 and N. tsunodae KUFC 9213 [30].
Dehydromevalonic acid (208) and lumichrome (209) ( Figure 30) were also isolated from the marine sponge-associated N. tsunodae KUFC 9213 [30]. Lumichrome is a derivative of the vitamin riboflavin and was found to activate the LasR quorum-sensing (QS) receptor. LasR normally recognizes the N-acyl homoserine lactone (AHL) signal. Amino acid substitutions in the LasR residues required for AHL binding altered the responses to both AHLs and lumichrome/riboflavin. Bacteria, plants, and algae commonly secrete riboflavin and/or lumichrome, raising the possibility that these compounds could serve as either QS signals or as interkingdom-signal mimics capable of manipulating QS in bacteria with a LasRlike receptor [64]. It is of note that, although lumichrome is commonly found in bacteria, plants, and algae, it is rarely reported from fungi.
In addition, 4(3H)-quinazolinone (210) (Figure 30) was isolated from the marine sponge-associated N. paulistensis KUFC 7897 [46]. It is interesting to note that although many quinazolinone-containing indole alkaloids have been isolated from many Neosartorya species, this is the first isolation of a simple 4(3H)-quinazolinone from the fungus of the genus Neosartorya.
The absolute configuration at C-19 was determined as 19S by X-ray analysis using CuKα radiation [20].

Biological Activity of Secondary Metabolites Produced by Fungi of the Genus Neosartorya
Some compounds isolated from members of the genus Neosartorya were tested for several biological/pharmacological activities, mostly in vitro. Like all other natural products, a majority of the compounds isolated from Neosartorya species were tested for in vitro anticancer/cytotoxic and antimicrobial activities. For practical aspect, they can be divided as follows:  (Figure 14), isolated from a culture extract of the soil-derived N. pseudofischeri against Hs683 (human glioblastoma), U373 (human glioblastoma), A549 (non-small cell lung cancer), MCF-7 (breast cancer), OE21 (esophageal cancer) and SKMEL28 (melanoma) cell lines. Compound 113 displayed in vitro anticancer activity in the range displayed by etoposide and carboplatin, whereas 98 exhibited less activity than 113 but was similar to that of carboplatin. Computer-assisted phase-contrast microscopy demonstrated that 113 displayed cytostatic and not cytotoxic effects in human U373 and A549 cells. Moreover, flow cytometry analysis confirmed the lack of cytotoxicity of 113, since no pro-apoptotic effects were observed with 113 in U373 and A549 cells. Flow cytometry analysis also showed that 113 did not modify cell cycle kinetics, such as the distribution of cells into the G1, S, and G2 phases of the cell cycle of A549 and U373 cells [35].
Aszonapyrones A (118) and B (119), sartorypyrones A (125) and B (126) (Figure 16), isolated from a culture extract of a soil-derived N. fischeri FO-4897, were tested for their antibacterial activity against Gram-positive and Gram-negative bacteria. Compounds 118, 125, and 126 displayed antibacterial activity against all tested Gram-positive bacteria viz. B. subtilis, Kocuria rhizophila, and Mycobacterium smegmatis, while 119 displayed antibacterial activity against only M. smegmatis. None of the tested compounds were active against Gram-negative bacteria, E. coli, and Xanthomonas oryzae [54].
Tryptoquivalines F (58) (Figure 17) from the marine spongeassociated N. tsunodae KUFC 9213, were evaluated for their antibacterial activity against Gram-positive S. aureus ATCC 25923 and B. subtilis ATCC 6633, and against Gram-negative E. coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853, as well as multidrug-resistant isolates from the environment. The potential synergism between these compounds and antibiotics was also evaluated against multidrug-resistant bacteria, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Among the meroditerpenes tested, only aszonapyrone A (118) and sartorypyrone A (125) displayed significant MIC values against Gram-positive bacteria. Compound 118 showed MIC values of 8 µg/mL against S. aureus ATCC 25923 and B. subtilis ATCC 6633, while 125 showed MIC values of 32 and 64 µg/mL, respectively, against the same reference strains. Interestingly, while 118 was active against both S. aureus MRSA (S. aureus B1 and B2) and Enterococcus spp. VRE isolates (E. faecalis W1 and W5), 125 did not show any inhibition of the growth of Enterococcus spp. VRE isolates in the range of concentrations tested. Very interestingly, the checkerboard method, as represented by the fractional inhibitory concentration (FIC) index, showed that a combination effect of 118 with the antibiotics oxacillin and ampicillin against MRSA and VRE isolates, respectively, was indifferent (ΣFIC > 0.5); however, 118 was able to decrease the MIC of each antibiotic tested and, thus, it may be considered as a partial synergistic effect. The association of 118 with vancomycin showed a clear synergistic effect (ΣFIC < 0.5) against the two VRE isolates (E. faecalis W1 and W5) tested. The combination of 125 with oxacillin and ampicillin against MRSA isolates was also found to be indifferent. Since the MIC of 125 against VRE was higher than 256 µg/mL, no checkerboard method was performed for this compound against the VRE isolates [46].
The effect of 118 and 125 at different concentrations, ranging from 2× to 1/4×MIC, on the biofilm formation by S. aureus ATCC 25923, B. subtilis ATCC 6633, and S. aureus B1, as well as E. faecalis W1 (in the case of 118), was evaluated. All the strains tested showed no biofilm formation in the presence of 2×MIC and MIC of 118 and 125. However, S. aureus ATCC 25923 and S. aureus B1 produced more biofilm in the presence of a subinhibitory concentration (1/2×MIC) of 118. Furthermore, S. aureus ATCC 25923 produced a significantly higher amount of biofilm in the presence of 1/2×MIC of 118, when compared to the control. Microscopic visualization of the biofilm produced by S. aureus ATCC 25923, using live/dead staining, revealed that the majority of the cells within the biofilm were viable and that large aggregates embedded in a matrix could be observed after 24 h. Interestingly, no biofilm was formed; also, no growth was observed in the presence of 118 at a concentration equal to its MIC. However, at a concentration of 1/2×MIC, it was possible to observe more biofilm in comparison to the control [46].
Examination of the structures of the meroditerpenes tested suggests the existence of some common features necessary for the antibacterial activity of this class of compounds. Although aszonapyrone A (118), aszonapyrone B (119), sartorypyrone C (120), chevalone B (122), and sartorypyrone A (125) all contain a 4-hydroxy-6-methyl-2H-pyran-2-one ring, only aszonapyrone A (118), chevalone B (122), and sartorypyrone A (125) have the β-acetoxyl group at C-3. In contrast to 118, 119, and 120, where the 4-hydroxy-6-methyl-2H-pyran-2-one ring is linked to the methylene group (CH 2 -15), this ring is connected to the perhydrophenanthrene portion by an ether bridge, forming a more rigid pentacyclic structure in chevalone B (122). Then again, both chevalone C (128) and sartorypyrone B (135) contain a 6-methyl-4H-pyran-4-one ring, also connected to the perhydrophenanthrene portion by an ether bridge. Therefore, it is apparent that the presence of a free 4-hydroxy-6-methyl-2H-pyran-2-one ring on C-15 and the β-acetoxyl group on C-3 of the perhydrophenanthrene portion are required for the antibacterial activity of this series of meroditerpenes [46].
Investigation of the influence of 183 in both the biofilm and its matrix spatial arrangement revealed a 98% reduction in the viability of the biofilm of S. aureus ATCC 29213 after 8 h of incubation with 183. On the contrary, there was only a 10% viability reduction after 24h of incubation. An investigation of 183 on biofilm extracellular polymeric substances revealed that after 8 h of incubation, 183 increased the number of channels homogeneously distributed by the biofilm. However, after 24 h of incubation, this biofilm did not maintain its structure and appeared to be quite similar to that of the control [58].
Glabramycins A (193), B (194), and C (195) (Figure 26), isolated from a soil-derived N. glabra (strains MF7030, F-155,700), were tested in the S. aureus antisense rpsD sensitized two-plate differential sensitivity assay. Compound 195 exhibited the most potent activity in this assay and showed a minimum detection concentration (MDC) of 62 µg/mL.  (Figure 30), isolated from the insectderived N. fischeri TJ403-CA8, were screened for antibacterial activity against six drugresistant microbial pathogens, including ESBL-producing E. coli, A. baumannii, P. aeruginosa, NDM-1-producing K. pneumoniae, methicillin-resistant S. aureus (MRSA), and E. faecalis. However, only 15, 18, 20, 32, 33, 102, and 211 displayed significant antibacterial activity against certain microbial pathogens, 211 being the most active against ESBL-producing E. coli, with a MIC value of 2.0 µg/mL, which was comparable to that of the clinically used antibiotic amikacin. The transmission electron microscopy (TEM) revealed that after 24 h of treatment of ESBL-producing E. coli with 211 at a concentration of 2 µg/mL, the cytoplasmic membranes of ESBL-producing E. coli cells were almost completely destroyed [20].  (Figure 30), isolated from the marine-derived N. fischeri 1008F1, were tested for their effects on the replication of tobacco mosaic virus (TMV) using the leaf-disc method. The tested compounds displayed a TMV replication inhibition ranging from 36.5 to 75.9% (ribavirin, the positive control, showed 45.2% inhibition). Compounds 178 and 196 showed IC 50 values of 0.26 and 0.63 mmol/mL, respectively [55].

Anti-Inflammatory Activity
The isolated compounds from the insect-derived N. fischeri TJ403-CA8 were screened for their anti-inflammatory potential by observing their inhibition of nitric oxide (NO) production, induced by lipopolysaccharides (LPS) in RAW264.7 cells. However, only fischeramide A (13) significantly inhibited LPS-induced NO production, with an IC 50 = 25 µM. Dexamethasone was used as a positive control [20].

Immunosuppressive Activity
The isolated compounds from the insect-derived N. fischeri TJ403-CA8 were also evaluated for their in vitro immunosuppressive activity in murine splenocytes stimulated by LPS and anti-CD3/anti-CD28 mAbs. Only fischeramide A (13) showed potential immunosuppressive activity in LPS and anti-CD3/anti-CD28 mAbs-activated murine splenocytes proliferation with IC 50 values of 7.08 and 6.31 µM, respectively, while the rest of the test compounds showed no activity at concentrations up to 40 µM [20].

Neuroprotective Activity
Glutamate is a well-known excitable neurotransmitter that can cause neuronal cell death during acute brain insults in neurodegenerative diseases. Fischerin (153) (Figure 20), from a culture extract of N. fischeri JS0553 at a concentration lower than 20 µM, was able to significantly recover the viability of mouse hippocampal neuronal (HT22) cells decreased by glutamate. Compound 153 also decreased a glutamate-induced increase in intracellular reactive oxygen species (ROS) and Ca + concentration. Moreover, 153 also significantly decreased the percentage of glutamate-induced apoptotic cells, suggesting that 153 efficiently prevented glutamate-induced apoptotic HT22 cell death. Additionally, it was found that the phosphorylation of mitogen-activated protein kinases (MAPKs), i.e., ERK, JNK, and p38, as increased by glutamate, was significantly diminished by 153, thus indicating that the inhibition of the sustained phosphorylation of MAPKs could be a key molecular mechanism of protection mediated by 153 against glutamate-induced HT22 cell death [27].

Lipid-Lowering Activity
Neosartoryone A (191) (Figure 26), isolated from a liquid culture extract of N. udagawae HDN13-313 by adding 5-azacytidine at 10 µM to the culture medium, was found to decrease lipid accumulation in HepG2 liver cells that was provoked by oleic acid. The effect of 191 is comparable to that of the current cholesterol-lowering drug, simvastatin, which was used as a positive control [61].

Enzyme Inhibitory Activities
The NADH-fumarate reductase (NFRD) system uses fumarate as a terminal electron acceptor in the mitochondrial electron transport chain and can generate ATP in the absence of oxygen. The system allows helminths to live in anaerobic circumstances inside host mammals. Since mammals do not have NFRD in their mitochondria, it is expected that a selective NFRD inhibitor could be a good anthelmintic drug candidate. Therefore, aszonapyrones A (118) and B (119), and sartorypyrones A (125) and D (126) (Figure 16), isolated from N. fischeri FO-5897, were tested for their inhibitory activity against mitochondrial respiratory enzymes using a submitochondrial particle of Acaris suum and bovine heart. Compounds 125 and 126 potently inhibited NFRD with IC 50 values of 0.6 and 1.7 µM, respectively. They also inhibited mammalian NADH oxidase with IC 50 values of 1.3 and 3.0 µM, respectively. Compounds 118 and 119 displayed moderate activity against NFRD with IC 50 values of 8.7 and 72.5 µM, respectively [54].

Insecticidal Activity
PF1223 (167) (Figure 21), isolated from the N. quadricincta strain PF1223, was tested for its capacity as a non-competitive GABA receptor antagonist, which is a target for insecticide. At 2.2 µM, 164 inhibited the specific binding of [ 3 H]EBOB to the housefly head membrane by 65%. It is worth mentioning that DBCPP, a non-competitive GABA receptor antagonist, displayed an IC 50 value of 3.41 µM for the GABA housefly receptor in the [ 3 H]EBOB assay [59].

Miscellaneous
Substance P (SP) is a potent agonist and an endogenous ligand for the neurokinin-1 (NK-1) receptor subtype. It induces a variety of physiological responses, such as salivation, vasodilation, and smooth muscle contraction, and is thought to be involved in pain transmission and the inflammatory response. Therefore, selective antagonists of SP might have potential as analgesics or anti-inflammatory agents. In this context, fiscalins A (69) (Figure 8), B (1) (Figure 1), and C (74) (Figure 8), isolated from N. fischeri, were assayed for their inhibitory activity on SP. Compounds 69, 1, and 74 inhibited the binding of 125 I-Bolton-Hunter SP to human astrocytoma U-373MG intact cells, with Ki values of 57, 174, and 68 µM, respectively [44].
The discussion of the secondary metabolites isolated from Neosartorya species, and their biological activities, are summarized in Tables 1 and 2 to facilitate readers to localize the compounds of interest and to compare them between different strains of the same species or between different species. Table 1 also includes the production culture media, to allow the readers to compare not only the sources of the fungi but also the influence of the medium on the secondary metabolite profiles of the strains and species.